Chronic endobronchial bacterial infections represent the primary cause of morbidity (declining lung function) and mortality in cystic fibrosis (CF). Inhaled antibiotics have become an increasingly attractive therapeutic modality compared to IV antibiotics, as inhaled drug is delivered directly to the site of infection while minimizing systemic exposure/toxicity. Nevertheless, short half-lives (typical t1/2 ~0.8 hr) in infected sputum limit antibiotic efficacy and necessitate multiple daily dosing. This shortcoming is especially critical for [unreadable]-lactam antibiotics, whose maximum efficacy relies on maintaining drug concentration above the minimum inhibitory concentration (MIC);the only approved inhaled [unreadable]-lactam (Cayston(r)) fails to sustain drug levels in CF sputum above MIC90 for even half the duration between dosing (3x daily). Previous attempts to achieve sustained local delivery of antibiotics were mostly based on polymeric or liposomal particles that do not possess Kala's proprietary mucus-resistant coatings (conventional particles, or "CP"). However, CP are extensively trapped at the very surface of the viscoelastic sputum lining the airways of CF patients, and are thus readily eliminated by mucociliary and cough-driven sputum clearance (thus precluding extended drug release). To overcome the sputum barrier, Hanes (co-founder of Kala) and coworkers pioneered the mucus-penetrating particle (MPP) technology, exclusively licensed to Kala. MPP rapidly penetrate into deep mucus layers and, thus, can persist longer and provide unprecedented drug-release durations at mucosal surfaces. A variety of MPP systems, including MPP composed entirely of excipients regarded by FDA as GRAS (Generally Recognized As Safe), have been engineered to penetrate purulent sputum expectorated from CF patients. In Phase I, we will build upon this work to formulate MPP for inhalation that slowly releases -lactam antibiotics. We expect that MPP will enhance bactericidal effectiveness against endobronchial bacterial infections by maintaining [unreadable]-lactam antibiotics above MIC90 in sputum for extended durations compared to free drug. In Specific Aim 1, we will formulate MPP that contain two common IV [unreadable]-lactams for CF lung infections. We will measure particle size, mobility in sputum, drug loading, drug release kinetics and storage stability. We will advance the MPP with the most suitable drug delivery characteristics to animal studies. In Specific Aim 2, we will administer [unreadable]-lactam- loaded MPP to the lungs of healthy rats, and confirm if drug levels in lung mucus are maintained above MIC90 for at least 24 hrs. Successful completion of these studies will lead to a Phase II proposal to develop [unreadable]-lactam MPP into a suitable pharmaceutical dosage form for extensive preclinical efficacy and safety testing in preparation for clinical trials. The overall goal is to develop a shelf-stable, sustained-release [unreadable]-lactam formulation that is efficacious with convenient 1W-daily dosing (by maintaining sputum drug levels above MIC90 for at least 24 hrs). By offering improved pharmacokinetics in the lung, we expect [unreadable]-lactam MPP will also improve therapies against bacterial infections in other pulmonary diseases, such as severe asthma and COPD. PUBLIC HEALTH RELEVANCE: Chronic endobronchial bacterial infections represent the primary cause of morbidity and mortality in cystic fibrosis. The only marketed [unreadable]-lactam antibiotic for inhalation (Cayston(r)) provides drug levels in the lung needed for maximally-effective bactericidal activity for only ~10-12 hours per day despite frequent administration (3 times daily). Kala Pharmaceuticals seeks to prove that our proprietary delivery systems can provide local delivery of [unreadable]-lactam antibiotics to the lungs that will markedly enhance current antibacterial therapy by providing a once-daily product that maintains drug concentration for 24h/day.